Central cannabinoid 1 (CB1) receptors are expressed in the brain. Their functions affect many neurological and psychological events. See, e.g., Goutopoulos et al., Pharmacol. Ther., 2002, 95, 103-7; and Shia et al., U.S. Pat. No. 7,834,046. Rimonabant, a central CB1 receptor antagonist, has been used to treat obesity. However, this drug has adverse psychiatric side effects. See e.g., Wu et al., Curr. Top. Med. Chem., 2011, 11, 1421-29.
CB1 receptors are also expressed in several peripheral tissues, e.g., liver, fat tissues, adipose tissues, and adrenal glands. See Marzo et al., Nat. Rev. Endocrinol., 2009, 5, 633-638. Peripheral CB1 receptor antagonists are potential drugs for treating many disorders, such as obesity, overweight, non-alcoholic fatty liver diseases, type 2 diabetes, nephropathy, kidney fibrosis, osteoporosis, and osteoarthritis. See e.g., Bioorg. Med. Chem. Lett. 2009, 19, 639-643; J. Clin. Invest. 2010, 120, 2953-2966; Bioorg. Med. Chem. Lett. 2010, 20, 4573-4577; and Diabetes 2010, 59, 1046-1054. It is widely accepted that such drugs should not have undesirable side effects as observed with rimonabant. See e.g., Wu et al., Curr. Top. Med. Chem., 2011, 11, 1421-29.
Safe and efficacious drug candidates remain to be identified from peripheral CB1 receptor antagonists, both synthesized and not yet synthesized.